A novel approach to enhancing the effectiveness of chemotherapy: combining curcumin with FOLFOX chemotherapy for metastatic colorectal cancer

FOLFOX (5FU/leucovorin/oxaliplatin) is standard first-line therapy for metastatic colorectal cancer (mCRC), with response rates of 50%. Factors limiting the use of oxaliplatin include chemo-resistance and severe dose-related peripheral neuropathy. New interventional strategies are required which can improve disease outcomes by increasing drug efficacy whilst avoiding toxicity. Curcumin is a constituent of turmeric. Mechanisms of chemopreventive action, extensively investigated in vitro and in vivo, provide compelling evidence that curcumin exhibits efficacy in preventing neoplastic conditions and can act synergistically with chemotherapy. Laboratory endpoints must be tested clinically. In preparation for a clinical trial combining curcumin with FOLFOX, 3 lines of investigation have been followed. In vitro analysis of CRC cell lines treated with the investigative agents has explored mechanisms of chemo-resistance and the efficacy of curcumin therein. The acceptability of oral curcumin to patients has been assessed, supported by sensitive Ultra Performance Liquid Chromatography (UPLC) evaluation of curcumin and its metabolites in biomatrices. Parallel methods of biomarker profiling of plasma and urine from patients with CRC by NMR, LC-MS/MS and HD-MS have been tested for their suitability as adjuncts to trials studying mCRC. The resultant clinical method, guided by these components, devised for the assessment of curcumin and FOLFOX has been presented alongside early trial data. In vitro, curcumin was observed to overcome oxaliplatin-resistance and increase efficacy. Mechanisms of action have been proposed and sub-populations of stem-like cells suggested as potential treatment targets. Safety and tolerability of a suitable curcumin regimen have been shown clinically. Sensitive analysis of plasma, urine and tissue curcuminoids has been achieved, and prolonged mucosal exposure revealed. The proteomic and metabonomic profiles of patients with CRC are distinct from controls and could feasibly be employed as surrogate endpoints to trials. A dose-escalation study has endorsed an acceptable regimen for an on-going randomised trial investigating curcumin with FOLFOX (“CUFOX”).